I intend to apply genetic methodology to ocular diseases. The following techniques will be used: definition of heterogeneity, study of systemic disease with ocular involvement, segregation analysis, linkage analysis, and screening of inbred populations. Prior to any meaningful histopathological, electonmicroscopical, or biochemical investigation, clinical entities have to be clearly delineated, using genetic information about the mode of inheritance, the clinical symptomatology at various ages in different family members, as well as ages of onset, rate of progression, and complications in different families. The conclusions will be refined by integration of laboratory results in the form of psychophysical testing for retinal degenerative disease, for example. Once there has been clear recognition of sub-groups, exact risk data with regard to recurrence and prognosis can be given. The study of systemic disease with ocular involvement will help to understand normal and pathologic biochemistry of the ocular tissues involved. In disease groups in which there is overlap between symptomatology so that entities with specific genetic and clinical prognosis cannot be delineated, segregation analysis has to be applied for estimates of recurrence risk and for detection of admixture of a proportion on non-genetic cases. Linkage analysis is of prime importance to ophthalmology, since it will permit indirect prenatal diagnosis of ocular diseases. Positive linkage information can also be helpful for identification of carriers at risk of developing hereditary ocular diseases prior to their having offspring. We also intend to undertake screening of inbred populations, in our case of the Old Order Amish of East Pennsylvania. In such isolated populations, recessive genes may, through drift, be at a very high gene frequency; thus permitting identification of new recessive disorders and delineation of their natural history. These approaches to ocular genetic diseases should, in selected instances, permit parents at risk to have normal children only. It should increase an individual's knowledge of his genetic constitution, which can help him to avoid complications.